The proposed research will examine whether metabotropic glutamate receptors (mGluR) have potential as therapeutic targets for treating age-related cognitive decline. The work will reveal mGluR actions in the evolved primate circuits that subserve the higher cognitive functions impaired by normal aging in monkeys and humans. The choice of drugs was advised by Dr. Jeffrey Conn, a world expert in mGluR pharmacology. We will examine how mGluR2/3 and mGluR5 agents influence prefrontal cortical (PFC) physiology and cognition in young vs. aged monkeys. This research is timely, as mGluR5 antagonists are being developed for Fragile X Syndrome, while mGluR2/3 agonists are being developed for schizophrenia. Thus, these compounds may have off-label use in the elderly to normalize calcium (Ca2+) and cAMP signaling in the aged PFC. A variety of data have shown evidence of increased Ca2+-cAMP signaling in the aged PFC, which reduces neuronal firing by opening Ca2+- and cAMP-regulated K+ channels on PFC synapses. mGluR5 and mGluR2/3 are localized both pre- and post-synaptically on highly evolved, layer III synapses in primate PFC. It is generally appreciated that mGluR5 antagonists and mGluR2/3 agonists can decrease excitotoxicity by pre-synaptic inhibition of glutamate release. However, these agents may also have beneficial actions at post-synaptic receptors in the primate PFC, reducing intracellular Ca2+ release and inhibiting cAMP signaling, respectively. Aim 1 will characterize the effects of mixed mGluR2/3 compounds (the agonist, (2R,4R)-APDC vs antagonist, LY341495) on Aim 1A) working memory and recognition memory performance, and Aim 1B) PFC neuronal firing, in young vs. aged monkeys to see if mGluR2/3 agonists may have potential as cognitive enhancers for the elderly. Aim 2 will begin to dissect mGluR2 vs. mGluR3 actions in primate dlPFC using newly available, selective mGluR2 vs. mGluR3 compounds, examining their effects on Aim 2A) cognitive performance and Aim 2B) neuronal firing. Aim 2C will also use immunoelectron microscopy (EM) to determine the pre- vs. post- synaptic location of mGluR2 vs. mGluR3 in highly evolved primate cortical circuits, their interactions with Ca2+- cAMP-K+ channel signaling proteins in PFC synapses, and any changes in distribution with advancing age. Aim 3 will characterize mGluR5 actions in primate dlPFC. These studies will examine the effects of the selective mGluR5 agonist, VU0360172, vs. the selective mGluR5 antagonists, MTEP or fenobam, on: Aim 3A) working memory and recognition memory abilities, and Aim 3B, PFC neuronal firing, in young and aged monkeys. Aim 3C will use immunoEM to localize mGluR5 in the young vs. aged primate cortex to see if mGluR5 co-localize with Ca2+-cAMP- K+ channel signaling proteins in spines, and whether there are any age- related changes in the pre- vs. post-synaptic distribution of these receptors. Preliminary data show improved cognitive performance and enhanced neuronal firing with low doses of the mixed mGluR2/3 agonist, APDC, or the mGluR5 antagonist, MTEP, in aged monkeys, consistent with potential therapeutic actions.